Hypercalcemia, an elevated level of calcium in the bloodstream, understandably causes concern. Calcium is an essential mineral that regulates numerous bodily functions, playing a role in bone strength, nerve signaling, and muscle contraction. The body tightly controls calcium levels, and a measurement outside the normal range indicates a disruption in this delicate balance. While the link between high calcium and serious diseases like cancer is a valid concern, malignancy is only one of many potential causes.
Defining Hypercalcemia and Recognizing Symptoms
A normal total serum calcium level typically falls within the range of 8.5 to 10.5 milligrams per deciliter (mg/dL). Hypercalcemia is defined as a measurement above this upper limit, but the severity of the elevation is categorized to guide clinical urgency. Mild hypercalcemia generally involves levels between 10.6 and 12.0 mg/dL, and a person may experience few or no noticeable symptoms. Moderate hypercalcemia is classified as a level between 12.1 and 14.0 mg/dL, where symptoms become more pronounced.
Symptoms can affect multiple organ systems, often summarized by the mnemonic “stones, bones, groans, and psychic moans.” “Stones” refers to the formation of kidney stones due to excessive calcium excretion, which can also lead to increased urination and thirst. “Bones” signals potential bone pain or weakness because calcium is being pulled from the skeleton. “Groans” describes gastrointestinal issues such as abdominal discomfort, nausea, and constipation. Finally, “psychic moans” encompasses neurological changes, including fatigue, lethargy, confusion, or depression.
The Most Common Cause: Non-Malignant Conditions
The vast majority of hypercalcemia cases are not related to cancer but are caused by Primary Hyperparathyroidism (PHPT). This condition results from one or more of the four small parathyroid glands, located in the neck near the thyroid, becoming overactive. These glands function as the body’s main calcium thermostat, releasing Parathyroid Hormone (PTH) to raise calcium levels when they drop too low.
The parathyroid gland malfunctions and produces too much PTH, regardless of the existing high calcium level. This excess hormone continuously signals the bones to release calcium and the kidneys to retain it, causing a persistent elevation in the blood. This is a slow-growing condition that often presents as a mild, long-standing elevation in calcium, which is a key factor distinguishing it from malignancy-associated hypercalcemia.
Several other non-malignant factors can temporarily or chronically raise calcium levels. Certain medications, such as lithium or thiazide diuretics, can interfere with calcium regulation. Excessive intake of Vitamin D supplements can also lead to hypercalcemia, as Vitamin D increases calcium absorption. Furthermore, prolonged immobilization, such as being bedridden, causes calcium to leach from the bones.
When Cancer Is the Cause: Specific Mechanisms
When cancer is the cause, it is typically a sign of advanced disease and is often characterized by a rapid, severe rise in calcium levels. Malignancy-associated hypercalcemia is primarily driven by two distinct mechanisms, which account for nearly all cancer-related cases. The most common mechanism, responsible for up to 80% of these cases, is known as Humoral Hypercalcemia of Malignancy (HHM).
HHM occurs when tumor cells secrete a hormone-like substance called Parathyroid Hormone-Related Protein (PTHrP). This protein structurally mimics natural PTH and binds to the same receptors in the bone and kidney. HHM is most frequently associated with solid tumors, including squamous cell carcinomas of the lung, head, and neck, as well as renal and ovarian cancers.
The second major mechanism is called Local Osteolytic Hypercalcemia, which accounts for 20% of malignancy-related cases. This occurs when cancer cells directly invade the bone marrow or metastasize to the bone tissue. These cells then release local factors that stimulate osteoclasts, which are the cells responsible for breaking down bone. The destruction of bone tissue releases a large amount of calcium directly into the bloodstream. This mechanism is most commonly seen in hematological malignancies like multiple myeloma and in solid cancers that frequently spread to the bone, such as breast cancer.
Diagnostic Steps to Pinpoint the Origin
Differentiating the origin of hypercalcemia requires a targeted laboratory investigation. The single most important test is the measurement of the intact Parathyroid Hormone (PTH) level, which immediately helps to categorize the hypercalcemia. If the PTH level is high or even within the normal range but inappropriately unsuppressed by the high calcium, it strongly points toward PHPT as the cause.
Conversely, if the PTH level is suppressed or very low, it indicates a non-parathyroid cause. In this scenario, further testing focuses on identifying the source of the excess calcium that is suppressing the PTH. This workup includes measuring the Parathyroid Hormone-Related Protein (PTHrP) level; an elevated PTHrP confirms a diagnosis of HHM.
Measurement of Vitamin D metabolites helps rule out excessive vitamin intake. If laboratory results strongly suggest malignancy, imaging studies like chest X-rays, mammograms, or further blood work may be ordered to look for an underlying tumor. If PHPT is suspected, specialized imaging of the neck may be used to locate the overactive parathyroid gland.